The α7 nAChRs are rapidly desensitizing ligand-gated ion channels that are abundantly expressed in the cerebral cortex and the hippocampus, a limbic structure intimately linked to attention processing and memory formation, see for example, Seguela et al. J. Neuroscience 1993 (13) pp 596-604. α7 nAChRs modulate neurotransmitter release and are responsible for direct fast excitatory neurotransmission. At the cellular level, activation of α7 nAChRs can regulate interneuron excitability, modulate the release of excitatory and inhibitory neurotransmitters, and contribute to neuroprotective effects.
Several lines of evidence indicate that impaired attention and cognition, which are characteristic of neurological and psychiatric disorders such as Alzheimer's disease (AD), see for example, Kem, Behav. Brain Res. 2000 (13) pp 169-81), schizophrenia, Parkinson's disease (PD), multiple sclerosis, attention deficit hyperactivity disorder (ADHD), mild cognitive impairment (MCI), age associated memory impairment (AAMI), may involve degeneration or hypo-function of cholinergic input, see for example, Rezvani and Levin Biological Psychiatry 2001 (49) pp 258-267. Moreover, genetic linkage has identified α7 nAChRs as a predisposing factor related to sensory gating deficits, see for example, (Freedman et al., Proceed. Nat. Acad. Sci. USA, 1997 (94) pp 587-92. Thus, targeting the α7 nAChRs represents a therapeutic strategy for ameliorating cognitive deficits associated with neurodegenerative and neuropsychiatric diseases.
A number of reports also suggest that α7 nAChRs mediate protection against neurotoxicity induced by amyloid beta and excitotoxic insults. Peripherally, α7 nAChRs are expressed in macrophages and their stimulation is essential for inhibiting the release of proinflammatory cytokines (e.g. TNF-a, IL-1) via the cholinergic anti-inflammatory pathway which is triggered in response to signals from the vagus nerve, see for example, (Wang, et al., J. of Neurochem. 2000 (75) pp. 1155-1161. Thus, the clinical use of positive modulators of the α7 nAChRs could also represent a strategy against inflammatory diseases.
Selective positive allosteric modulation (PAM) of the α7 nAChR is a recently proposed therapeutic approach for treating these disease states. A key advantage of this approach is that modulation only occurs in the presence of endogenous agonist thereby preserving the temporal and spatial integrity of neurotransmission, see for example, Picciotto, 2003 Trends in Pharm. Sciences, September 24(9), pp 493-499). Several different profiles have been described for PAMs of the α7 nAChR ranging from Type I modulators that predominately affect the peak current and may also increase channel affinity for the agonist, to Type II modulators that affect the peak current, delay the desensitization of the receptor and may reactivate desensitized receptors, see for example, Gronlein et al., Mol Pharmacol 2007 (72) pp. 715-724. Several PAMs have been described in the literature with some Type I examples including: 5-Hydroxyindole (Gurley et al., Soc Neurosci Abs. 2000, 716, p. 15), NS-1738 (Timmerman, et al., J Pharmacol Exp Ther, 2007 (323) pp 294-307), Ivermectin (Krause et al., Mol Pharmacol 1998 (53), pp 283-294), Galantamine (Lopes, et al., J Pharmacol Exp Ther. 2007 (322), pp. 48-58) and Genistein (Charpantier, et al., J Neurosci 2005 (25), pp 9836-9849); Type II examples including PNU-120596 Hurst, et al., 2005 (25), pp 4396-4405), TQS (Gronlien, et al., Mol Pharmacol, 2007 (72), pp 715-724) 2007, and A-867744 (Faghih, et al., J Med Chem 2009, (52), pp. 3377-3384), and some intermediate examples: SB-206553 (Dunlop, et al., J. Pharmacol. Exp Ther., 2009 (328), pp. 766-776) and JNJ-1930942 (Dinklo, et al., J Pharmacol Exp Ther., 2011 (336), pp. 560-574). 2011; 336:560-74). In general, PAMs demonstrate enhanced receptor responses to the endogenous ligands acetylcholine and choline, as well as to nicotine and other agonists.
The present invention seeks to address some of the shortcomings of the prior art compounds and is directed to a new class of compounds which exhibit positive modulation of α7 nAChR.